Many advances have been described in recent years for the treatment of dermal wounds, such as lacerations, incisions, burns, and sores. Such advances have addressed, for instance, the desirability of keeping the wound moist, yet not water-logged, keeping it free from microbial contamination, and so on. The treatment of wounds has evolved to the use of such things as inert dressings having nearly skin-like properties in terms of flexibility, moisture vapor transmission, low irritation, protection from infection, and so on.
In addition to inert dressings themselves, a variety of compounds, adjuvants, factors, and the like have been described that are either used alone or in conjunction with inert dressings, e.g., in order to provide antimicrobial activity, absorbancy, promote tissue regeneration, and so on. One approach involves the use of the polysaccharide chitin and its derivatives, particularly the deacetylated form chitosan, to enhance wound healing. U.S. Pat. No. 3,903,268, for example, describes wound healing compositions containing chitin, depolymerized chitin, or chitin derivatives.
U.S. Pat. No. 4,605,623 describes a method for cultivating myocytes in suspension involving the use of an aqueous chitosan solution sufficient to enable the three-dimensional growth of such myocytes and to inhibit undesired cells such as fibroblasts, tumor cells, mycoplasma and bacteria. U.S. Pat. No. 4,394,373 describes the use of chitosan, in liquid or powder form, to achieve hemostasis in wounds, vascular grafts, cardiac valves, and the like.
Wounds such as dermal ulcers pose a particular problem in terms of their treatment. Such wounds include, for instance, sores that are formed by the continual pressure of the body on underlying skin, an example being "bed sores", that often appear in patients confined for long periods of time in restricted positions. If not effectively treated, such wounds can become large, invasive, weeping sores that can progress so deeply so as to affect and even expose underlying tissues or bone. They often produce a large amount of exudate and can become a site of infection, including life-threatening infections.
A variety of approaches have been described for the treatment of dermal ulcers, some of which involve packing the open void with a dressing that is intended to generally conform to the space formerly occupied by normal tissue. Early approaches included the use of medicated gauze to pack such wounds. More recently, compositions having the ability to fill a deep wound and to absorb wound exudate have been used.
A commercially-available product, "Bard Absorption Dressing", available from C. R. Bard, Inc., Berkeley Heights, NJ, is sold as a dry powder for use in treating or packing wounds. This product is described as a "dry polysaccharide derivative made by graft copolymerization of carboxyl and carboxamide groups onto cornstarch", and is sold in a two-component pouch containing the dry powder in one portion and water in the other. The two components need to be mixed just before use. The resultant gel-like composition has a useful consistency. However, it absorbs water or exudate at a rapid rate and may desiccate the wound, thereby causing discomfort to the patient. Moreover, the composition does not provide antimicrobial activity or wound-healing properties, rather it is described as being "compatible with topical medications".
Other commercially available products include
(1) "Spand-Gel Granulated Gel", available from Medi-Tech International Corp., Brooklyn, NY, which is described as a hydrogel composed of sterile water bound by polyacrylamide, and containing "cross-linked super absorbent poly-carbohydrate beads";
(2) "Debrisan.RTM. Wound Cleaning Beads and Paste", available from Johnson & Johnson Co., New Brunswick, NJ, which is described as a mixture of polyethylene glycol with "spherical hydrophilic beads of dextranomer";
(3) "Pharmaseal HydraGran Absorbent Dressing", available from American Pharmaseal Co., Valencia, CA, which is described as being able to absorb up to 22 times its weight in human serum, and able to "trap bacterial contamination and necrotic debris"; and
(4) "Geliperm wound management system", available from Geistlich-Pharma, Wolhusen, Switzerland, which is described as "an inert hydrogel formulation composed of sterile water bound by a polyacrylamide/agar network", and is available as both a smooth, transparent gel sheet and as a "granulate" having gel-like consistency.
It does not appear that any of the commercially-available products described above themselves contain ingredients having anti-microbial activity, although certain of the manufacturers claim to achieve an antimicrobial effect in various ways, e.g., by the physical removal of bacteria (by means of the suction force of an absorbent composition); by creating a physical barrier to the entry of bacteria, and so on.
Other dressings include "Hydra Gran Absorbent Dressing" (American General Health Care, Glendale, CA); "Wound Exudate Absorber" (Hollister, Inc., Libertyville, IL); "Duoderm Hydroactive Granules" (ConvaTec, Princeton, NJ); and "Comfeel Ulcus System" (Coloplast, Inc., Tampa, FL).
Yet other products are described in the patent literature. For instance, U.S. Pat. No. 4,538,603 describes, inter alia, the use of a granular product for packing a wound site, which can then be covered by the occlusive dressing described therein. Among the granular products described are water dispersible hydrocolloid materials such as sodium or calcium carboxymethylcellulose, pectin, gelatin, guar gum, locust bean gum, collagen, and karaya gum. Such materials are also included in the adhesive layers of the dressing itself. The purpose of these materials is described as providing "wet tack" between the dressing and the wound itself, thereby ultimately bonding the dressing to the skin.
Among the formulations that have been described for use in treating wounds such as dermal ulcers, are formulations containing chitin or its derivatives, although none appear to have gained wide commercial acceptance. Balassa et al., "Applications of Chitin and Chitosan in Wound-Healing Acceleration", pp. 296-305, in Proceedings of the First International Conference on Chitin/Chitosan, Ed. Muzzarelli et al., MIT Sea Grant Report MITSG 78-7 (May 1978) describes the acceleration of healing in both "slow healing and non-healing wounds (ulcers)", by chitin, chitosan and depolymerized chitin.
U.S. Pat. No. 4,659,700 discloses gels or gel-like membranes prepared by dissolving chitosan in acid-water-glycerol solutions and then neutralizing the solutions with base. The gels are described as being useful carriers for a variety of other medicaments, but clearly would not themselves be very absorbent of wound exudate.
In each instance of which applicant is aware in which chitosan has been used with another polyelectrolyte to prepare a composition, the composition is either (1) not a homogeneous gel, e.g., is instead a dry, aqueous, or multiphasic (i.e., biphasic or greater) composition, or (2) is a gel or gel-like composition, but is formed by a separation, precipitation, or drying of the composition from a liquid phase, e.g., by what would be termed, for purposes of this discussion, "syneresis".
EPO Patent Application number 85101490 2, for instance, describes the preparation of capsules having a semipermeable membrane, and a liquid core which contains a biologically active material such as microbial cells. The capsules are formed, e.g., by the dropwise combination of an anionic polymer composition, such as alginate or carrageenan, with a cationic polymer composition, such as chitosan, where one of the compositions contains the active material. The resultant capsules contain a liquid core and are used in an aqueous medium.
In another example, described in U.S. Pat. No. 4,501,835, a polyacrylic acid/chitosan polyelectrolyte complex is prepared in aqueous acidic solution. A membrane or film can be formed by drying a coating of the complex.
Dry chitosan-containing compositions are described in EPO Patent Application no. 86300039.4, for a sustained release preparation containing (1) chitin, chitosan, or a mixture thereof, (2) at least one anionic polymer compound, and (3) at least one pharmaceutically active agent. These components are described as being in the form of "for example, tablets, granules, grains, powders, dental cones, films, or hard capsules."
In the only such instance to also involve the use of a chitosan/polyelectrolyte composition for wound healing, U.S. Pat. No. 4,570,629 describes hydrophilic biopolymeric copolyelectrolytes made up of: (a) a water-soluble linear anionic protein polyelectrolyte component derived from keratin, and (b) a water-soluble linear cationic biopolymer polyelectrolyte component. When the first component is contacted in the presence of water with the second component, "the components spontaneouslY rearrange themselves into a water-insoluble, water-swellable, solid coherent mass."
The cationic component is derived from at least one biopolymer selected from a glucosaminoglycan and collagen, and is described as including chitosan acetate, collagen acetate, and mixtures thereof. In their hydrated form, such copolyelectrolytes are described as stress-durable hydrogels that are useful as wound dressings.
It is clear that, to date, there still exists a need for a single composition that provides the properties desirable for an effective, versatile, wound filling material for use with wounds such as dermal ulcers, e.g. in terms of viscosity, absorbancy, antimicrobial activity, wound healing capability, ability to be effectively sterilized, and so on.